EP0574494A1 - Indoles utiles comme antagonistes du facteur d'activation des plaquettes - Google Patents

Indoles utiles comme antagonistes du facteur d'activation des plaquettes

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Publication number
EP0574494A1
EP0574494A1 EP92906944A EP92906944A EP0574494A1 EP 0574494 A1 EP0574494 A1 EP 0574494A1 EP 92906944 A EP92906944 A EP 92906944A EP 92906944 A EP92906944 A EP 92906944A EP 0574494 A1 EP0574494 A1 EP 0574494A1
Authority
EP
European Patent Office
Prior art keywords
pyridinyl
oyl
thiazolid
indole
dimethylcarbamoyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP92906944A
Other languages
German (de)
English (en)
Other versions
EP0574494A4 (en
Inventor
James B. Summers
George S. Sheppard
James G. Phillips
Daisy Pireh
Douglas H. Steinman
Paul D. May
Denise E. Guinn
H. Robin Heyman
George M. Carrera, Jr.
Steven K. Davidsen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Laboratories
Original Assignee
Abbott Laboratories
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Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP0574494A1 publication Critical patent/EP0574494A1/fr
Publication of EP0574494A4 publication Critical patent/EP0574494A4/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to compounds having pharmacological activity, to compositions containing these compounds, and to a medical method of treatment employing the compounds and compositions. More particularly, this invention concerns certain pyridylthiazolidine, pyridyldithiolane, and pyridylpyrrolidine compounds and their salts which have platelet activating factor (PAF) antagonist activity, to pharmaceutical compositions containing these compounds, and to a method of treating PAF-mediated disorders.
  • PAF platelet activating factor
  • Platelet activating factor is a phospholipid released from human and other animal cells and is an acetylglyceryl ether of phosphorylcholine as represented by the following formula:
  • n 15 or 17.
  • PAF is physiologically active and causes contraction of the airway smooth muscle, increased vascular permeability, platelet aggregation, hypotension and the like.
  • endotoxin- and IgG-induced shock septic shock
  • asthma and pulmonary dysfunction acute inflammation
  • transplanted organ rejection thrombosis
  • cardiac anaphylaxis gastrointestinal ulceration
  • allergic skin diseases retinal and corneal diseases
  • chemically induced liver cirrhosis and ovimplantation in pregnancy.
  • A is methylene, hydroxymethyl, or carbonyl
  • X is sulfur, or NR-5 where R-5 is hydrogen, alkyl of from one to six carbon atoms, formyl, alkoyl of from one to six carbon atoms, alkylsulfonyl of from one to six carbon atoms, trihaloacetyl, or -C(O)NR6R? o where R ⁇ and R? are independently selected from hydrogen and alkyl of from one to six carbon atoms.
  • the group Y is sulfur or methylene.
  • R is selected from (a) hydrogen; (b) alkyl of from one to six carbon atoms; (c) -(CH2)nC(O)NR6R7 where R6 and R? are as previously defined and where n is from zero to four, (d) -(CH2)nC(O)OR ⁇ where R*--* is alkyl of from one to six carbon atoms, phenyl, optionally substituted with alkyl of from one to six carbon atoms, alkoxy of from one to six carbon atoms, or halogen; phenylalkyl in which the alkyl portion contains from one to four carbon atoms, alkoxy of from one to six carbon atoms, or halogen, and where n is as previously defined; (e) -(CH2)nC(O)R ⁇ where n is as previously defined and R ⁇ is hydrogen or alkyl of from one to six carbon atoms; (f) -(CH2)mCOOH where m is from one to four, (g)
  • R! is hydrogen or B with the proviso that one of R or R 1 is B, but R and R 1 are not both B.
  • R2 is selected from hydrogen or alkyl of from one to six carbon atoms.
  • R3 and R ⁇ are independently selected from the group consisting of (a) hydrogen; (b) halogen; (c) alkyl of from one to six carbon atoms; (d) alkoxy of from one to six carbon atoms; (e) alkoyl of from one to six carbon atoms; (f) cyano; (g) phenylalkoxy in which the alkoxy portion contains from one to six carbon atoms; (h) phenoxy; (i) benzoyl, optionally substituted with alkyl of from one to six carbon atoms, alkoxy of from one to six carbon atoms, or halogen; (j) -NR ⁇ R?
  • R6 and R 7 are as previously defined; (k) -C(O)OR9 where R ⁇ is as previously defined; and (1) phenyl, optionally substituted with alkyl of from one to six carbon atoms, alkoxy of from one to six carbon atoms, or halogen.
  • the present invention provides pharmaceutical compositions useful for the treatment of PAF-mediated disorders comprising a therapeutically effective amount of a compound of formula I above in combination with a pharmaceutically acceptable carrier.
  • the present invention provides a method of inhibiting PAF activity by administering to a host mammal in need of such treatment a PAF-inhibiting effective amount of a compound of structure I above.
  • a method of treating PAF-mediated disorders including septic shock, asthma, anaphylactic shock, respiratory distress syndrome, acute inflammation, delayed cellular immunity, parturition, fetal lung maturation, and cellular differentiation by administering to a host mammal in need of such treatment a therapeutically effective amount of a compound of structure I above.
  • Preferred compounds of formula II are those in which A is carbonyl, X is NR-5 (where R-5 is as defined above) and Y is sulfur, R2 is hydrogen or alkyl of from one to six carbon atoms, and R3 is hydrogen, halogen, or phenylalkoxy in which the alkoxy portion contains from one to six carbon atoms, and R ⁇ is hydrogen.
  • Particularly preferred are compounds of formula II in which R2 is hydrogen or methyl; R3 is selected from hydrogen, 5-phenylalkoxy, or 5-halo; and R**-' is hydrogen.
  • compounds of the present invention are represented by formula HI:
  • R-5 is as defined above and Y is sulfur
  • R2 is hydrogen
  • R is selected from hydrogen, -(CH2) n C(O)NR 6 R 7 (where n, R 6 and R 7 are as defined above), ⁇ (CH2)nC(O)OR 8 (where n and R 8 is as defined above), or -(CH2)mCOOH (where m is as defined above)
  • R3 is hydrogen, alkyl of from one to six carbon atoms, or phenylalkoxy in which the alkoxy portion contains from one to six carbon atoms
  • R 4 is hydrogen.
  • Particularly preferred compounds of formula III are those in which R and R5 are hydrogen, -C(O)N(CH 3 ) 2 , -CH2C(O)N(CH 3 ) 2 , -CH2COOH, -CH2CH2COOH or t -butoxycarbonyl; R--* * is hydrogen, phenylmethoxy, or methyl; R2 and R 4 is hydrogen.
  • Examples of compounds contemplated as falling within the scope of the present invention include, but are not necessarily limited to: l-[2-(3-pyridinyl)thiazolid-4-oyl]indole; 1 -[2-(3-pyridinyl)thiazolid-4-oyl]-2,5-dimethylindole; l-[2-(3-pyridinyl)thiazolid-4-oyl]-4-chloroindole; l-[2-(3-pyridinyl)thiazolid-4-oyl]-4-bromoindole; l-[2-(3-pyridinyl)thiazolid-4-oyl]-5-chloroindole; l-[2-(3-pyridinyl)thiazolid-4-oyl]-6-fluoroindole; 1 -[2-(3-pyridinyl)thiazolid-4-oyl]-6-chloroindole; l-[
  • carbamoyl refers to a structure of formula -CONR6R7 wherein R ⁇ and R? are independently selected from hydrogen or a straight or branched alkyl radical of from one to six carbon atoms.
  • Representative examples of carbamoyl groups include - C(O)NH2» N,N-dimethylcarbamoyl, N-tert-butylcarbamoyl, N-methyl-N-ethylcarbamoyl and the like.
  • carboalkoxy refers to a structure of formula -C(O)OR 8 wherein R 8 is a straight or branched alkyl radical of from one to six carbon atoms, phenyl or substituted phenyl.
  • Representative examples of carboalkoxy groups include carbomethoxy, carboethoxy, carbo(w ⁇ ?-propoxy), carbobutoxy, carbo(_?ec-butoxy), carbo( _? ⁇ -butoxy), carbo(r -butoxy), phenoxycarbonyl, and the like.
  • alkoyl refers to formyl and radicals of the structure -C(O)-alkyl in which the alkyl portion is a straight or branched alkyl group of from one to six carbon atoms.
  • Representative examples of alkoyl groups include formyl, acetyl, propionyl, butyryl, wo-butyryl, pivaloyl, and the like.
  • alkoxy refers to a lower alkyl group, as defined herein, which is bonded to the parent molecular moiety through an oxygen atom
  • alkoxy groups include methoxy, ethoxy, t -butoxy, and the like.
  • alkyl refers to straight or branched chain radicals derived from saturated hydrocarbons by the removal of one hydrogen atom.
  • Representative examples of alkyl groups include methyl, ethyl, n-propyl, w ⁇ -propyl, n- butyl, sec-butyl, wo-butyl, rerr-butyl, and the like.
  • alkylsufonyl is used herein to mean -SO2(alkyl) where the alkyl group is as defined above.
  • Representative examples of lower alkylsufonyl groups include methylsulfonyl, ethylsufonyl, w ⁇ propylsulfonyl and the like.
  • PAF-related disorders and “PAF-mediated disorders” are used herein to mean disorders related to PAF or mediated by PAF, including septic shock, asthma, anaphylactic shock, respiratory distress syndromes, acute inflammation, delayed cellular immunity, parturtition, fetal lung maturation, and cellular differentiation.
  • phenylalkoxy is used herein to mean an phenyl group appended to an alkoxy radical as previously defined. Representative examples of phenylalkoxy groups include phenylmethoxy (i.e. benzyloxy), 1-phenylethoxy, 2-phenylethoxy, 2- phenylpropoxy, and the like.
  • salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, Iactiobionate, laurylsulphonate salts and the like.
  • sulfate bisulfate
  • phosphate nitrate
  • acetate oxalate
  • valerate valerate
  • oleate palmitate
  • stearate laurate
  • borate benzoate
  • lactate lactate
  • phosphate tosylate
  • citrate maleate
  • fumarate succinate
  • tartrate naphthylate
  • mesylate glucoheptonate
  • individual enantiomeric forms of compounds of the present invention can be separated from mixtures thereof by techniques well known in the art.
  • a mixture of diastereomeric salts may be formed by reacting the compounds of the present invention with a optically pure form of an acid, followed by purification of the mixture of diastereomers by recrystallization or chromatography and subsequent recovery of the resolved compound from the salt by basification.
  • the optical isomers of the compounds of the present invention can be separated from one another by chromatographic techniques employing separation on an optically active chromatographic medium.
  • the members of the pyridylthiazolidine class can be obtained as the prefered pure R -enantiomeric form by choosing the naturally occuring R - enantiomer of the amino acid cysteine as the starting material (vide infra).
  • the present invention also provides pharmaceutical compositions which comprise one or more of the compounds of formula I above formulated together with one or more non-toxic pharmaceutically acceptable carriers.
  • the pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray.
  • parenteral administration refers to modes of 1 1 administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraa ⁇ icular injection and infusion.
  • compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, 5 suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl 1 o oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of 15 microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. 20 In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection.
  • adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug 30 release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a 35 bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and gly
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Examples of embedding compositions which can be used include polymeric substances and waxes.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, w ⁇ propyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifier
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated wostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.
  • Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required.
  • Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration.
  • the selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. Generally dosage levels of about 0.001 to about 100, more preferably of about
  • the effective daily dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.
  • the compounds of this invention are synthesized by reaction Schemes I though XIII as illustrated below. It should be understood that that X, Y, A, Ri, and R2 as used herein correspond to the groups identified by Formula I.
  • the compounds of Formula (I) may be prepared using the reactions and techniques described in this section. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. It is understood by those skilled in the art of organic synthesis that the functionality present on the heterocycle and other portions of the molecule must be consistent with the chemical transformation proposed. This will frequently necessitate judgement as to the order of synthetic steps, protecting groups required and deprotection conditions.
  • L-cysteine (1) is condensed with 3-pyridine aldehyde (2) to produce 2-(3-pyridinyl)-4-thiazolidinecarboxylic acid (3).
  • the thiazolidine nitrogen is protected with an appropriate group, preferably carbo-tert-butoxy (BOC) with di-t -butyl dicarbonate (4).
  • the resulting 2-(3-pyridinyl)-3-rert- butoxycarbonyl-4-thiazolidinecarboxylic acid (5) is converted to an active ester (7), preferably the acid chloride (W is Cl), through the action of oxalyl chloride, or the N- hydroxysuccinimide ester (W is O-succinimide) through the action of N- hydroxylsuccinimide and a coupling agent such as dicyclohexylcarbodiimide or bis (2- oxo-3-oxazolidinyl)phosphinic chloride.
  • W acid chloride
  • W N- hydroxysuccinimide ester
  • a coupling agent such as dicyclohexylcarbodiimide or bis (2- oxo-3-oxazolidinyl)phosphinic chloride.
  • the anion of an unsubstituted or substituted indole (8) is prepared by the reaction of the indole with a strong base, preferably sodium hydride (9) and the this anion is reacted with the active ester (7) to give the l-[2-(3- pyridinyl)-3-rert-butoxycarbonyl-thiaz-4-oyl]indole (10).
  • the BOC protecting group can be removed with acid, preferably HC1, to the produce l-[2-(3-pyridinyl)-thiazolid- 4-oyl]indole (11).
  • 2-(3-pyridinyl)-3-rert- butoxycarbonyl-4-thiazoIidinecarboxylic acid (5) is converted to the acid chloride (7), preferably by treatment with oxalyl chloride or thionyl chloride.
  • the acid (5) may first be converted to its salt by treatment with a base, such as sodium hydride, and then treated with oxalyl chloride or thionyl chloride to afford 7.
  • an active ester of 2-(3- pyridinyl)-3-terr-butoxycarbonyl-4-thiazolidinecarboxylic acid (7) preferably the acid chloride (W is Cl) or the N-hydroxylsuccinimide ester, prepared as described in scheme I
  • W is Cl
  • N-hydroxylsuccinimide ester prepared as described in scheme I
  • the anion is prepared from the indole and a strong base, preferably ethyl magnesium bromide.
  • the BOC group is removed from 13 by treatment with an acid, preferably HC1.
  • an active ester of 2-(3- pyridinyl)-3-tert-butoxycarbonyl-4-thiazolidinecarboxylic acid (7) preferably the acid chloride (W is Cl), prepared as described in scheme I, is treated with the zinc salt of an unsubstituted or substituted indole (8) in a solvent, preferably diethyl ether, to give a 3- [2-(3-pyridinyl)-3-rert-butoxycarbonylthiazolid-4-oyl]indole (13).
  • the zmcsalt is prepared from the indole and a strong base, preferably ethyl magnesium bromide, followed by the addition of an anhydrous inorganic zinc salt, preferably zinc (II) chloride .
  • the BOC group is removed from 13 by treatment with an acid, preferably HC1.
  • 2,3-dibromopropionic acid (14) is treated with NaSH followed by esterification with HC1 in methanol to give methyl 2,3- dimercaptopropenonate (IS).
  • This dithiol (15) is condensed with 3-pyridine carboxaldehyde in the presence of an acid catalyst, preferably /Moluenesulfonic acid to afford methyl 2-(3-pyridinyl)-4-dithiolanecarboxylate (16).
  • the dithiolane ester is hydrolyzed to the coiresponding acid (17) by treatment with aqueous base, preferably lithium hydroxide.
  • 2-(3-Pyridinyl)-4-dithiolanecarboxylic acid (17) is then converted to an active ester (18), preferably the imidazolide (W is 1-imidazole) by treatment with carbonyl diimidazole.
  • the anion of an unsubstituted or substituted indole (8) is prepared by treatment with a strong base, preferably sodium hydride, and this is reacted with the active ester (18) to afford l-[2-(3-pyridinyl)-dithiolan-4-oyl]indole (19).
  • an indole without a nitrogen substituent is protected, preferably as the BOC from treating with di-rerr-butyl dicarbonate (4) or as the benzenesulfonyl from treating with benzenesulfonyl chloride and a base, preferably KOH, to give 22.
  • This protected indole is treated with a halogenating agent, preferably N-bromosuccinimide, then metallated with an organolithium reagent, preferably terr-butyl lithium, at -78°C, and then reacted with the active ester 18, preferably theN-methyl-N-methoxy amide (W is ⁇ (CH3)OCH3) to afford the l-protected-3-[2-(3-pyridinyI)-dithiolan-4-oyl]indole (23).
  • a halogenating agent preferably N-bromosuccinimide
  • the BOC or benzenesulfonyl group can be removed by treatment with a nucleophile, preferably sodium methoxide, to afford 3-[2-(3-pyridinyl)-dithiolan-4-oyl]indole (24).
  • a nucleophile preferably sodium methoxide
  • a 3-[2-(3-pyridinyl)-3-tert- butoxycarbonylthiazolid-4-oyl]indole (13) without a substiment on the indole nitrogen is treated with a strong base, preferably potassium hexamethyl disilazide, followed by treatment with an alkyl halide (RX) or an active ester (RCOX), such as an acid chloride, an isocyanate (RNCO), or an alkylsulfonyl halide (RSO2X) to give the indole with a substiment on the indole nitrogen (25).
  • RX alkyl halide
  • RCOX active ester
  • RSO2X alkylsulfonyl halide
  • the BOC group is removed from 20 by treatment with an acid, preferably HC1 to afford 26.
  • reaction scheme VHI describes transformations similar to scheme VII, except using the dithiolane 24 instead of the thiazolidine 13 to a afford 3-[2-(3- pyridinyI)-dithiolan-4-oyl]indole with a substituted indole nitrogen (27).
  • l-tert-butoxycarbonyl-3-[2-(3- pyridinyl)-thiazolid-4-oyl]indole (28) is treated with a alkyl halide (RX), an alkoyl halide (RCOX), an isocyanate or an alkyl sulfonyl halide to afford the substituted compound 29 in the presence of a base such as trie thy lamine.
  • RX alkyl halide
  • RCOX alkoyl halide
  • the BOC group can be removed by treating with an acid, preferably HCl, to yield the substituted 3-[2-(3-pyridinyl)-thiazolid- 4-oyl]indole (30).
  • an unsubstituted or substimted indole is treated with a base, preferably sodium hydride and then reacted with an aryl sulfonyl chloride (ArS ⁇ 2Cl), preferably benzenesulfonyl chloride to yield the sulfonyl indole 31.
  • a base preferably sodium hydride
  • an aryl sulfonyl chloride preferably benzenesulfonyl chloride
  • This compound (31) is then treated with n-butyl lithium followed by an active ester of 2-(3-pyridinyI)-3-rert-butoxycarbonyl-4-thiazolidinecarboxylic acid (7, X is N-COtbutyl) or of 2-(3-pyridinyl)-4-dithiolanecarboxylic acid (18, X is S) to yield compound (32).
  • the sulfonyl protecting group can be removed by hydrolysis in aqueous base, preferably lithium hydroxide to afford a 2-[2-(3-pyridinyl)-3-re/?-butoxy- carbonylthiazolid-4-oyl]indole or a 2-[2-(3-pyridinyl)-dithiol__n-4-oyl]indole (30).
  • aqueous base preferably lithium hydroxide
  • he BOC group can be removed by treating with an acid, preferably HCl, to yield the 2-[2-(3-pyridinyl)-thiazolid-4-oyl]indole.
  • an unsubstituted or substituted BOC-D-tryptophan is reduced, preferably with diborane to yield a tryptanol (35).
  • This compound (35) is treated with thioacetic acid, triphenyl phosphine, and a dialkylazodicarboxylate, preferably di-wopropyl azodicarboxylate to yield the thio acetate, 36.
  • the thio ester (36) is hydrolyzed with hydroxide, preferably sodium hydroxide in methanol to yield a thiol, 37, and then the BOC group is cleaved with acid, preferably HCl, to yield an amino thiol, 38.
  • This compound (38) is condensed with 3- pyridine carboxaldehyde to give a 3-[2-(3-pyridinyl)-thiazolid-4-oyl]methylindole (39).
  • the resulting 1-rert- butoxycarbonyl-2-(3-pyridinyl)-5-pyrrolidinecarboxylic acid (41) is converted to an active ester (7), preferably the acid chloride (W is Cl), through the action of oxalyl chloride, or the N-hydroxysuccinimide ester (W is O-succinimide) through the action of N-hydroxylsuccinimide and a coupling agent such as dicyclohexylcarbodiimide or bis (2- oxo-3-oxazolidinyl)phosphinic chloride.
  • W acid chloride
  • W N-hydroxysuccinimide ester
  • a coupling agent such as dicyclohexylcarbodiimide or bis (2- oxo-3-oxazolidinyl)phosphinic chloride.
  • the anion of an unsubstituted or substimted indole (8) is prepared by reacting the indole with a strong base, preferably ethyl magnesium bromide.
  • the anion (8) is reacted with the active ester (42) to yield 3-[l-rert- butoxycarbonyl-2-(3-pyridinyl)-pyrrolindin-5-oyl]indole (43).
  • the BOC group can be removed by treating 43 with an acid, preferably HCl to yield 3-[2-(3-pyridinyl)- pyrrolidin-5-oyl]indole (44).
  • Citrated whole rabbit blood was obtained from Pel-Freez (Rogers, AR). Rabbit platelets were prepared by centrifugation and washing. The platelets were lysed by freeze-thawing and sonication; platelet membranes were prepared by centrifugation and washing. Final membrane preparations were stored frozen in 10 mM Tris/5 mM MgCl?/ mM EDTA (TME buffer, pH 7.0) with 0.25 M sucrose added for membrane stabilization
  • the standard PAF receptor binding assay contained 10 ⁇ g platelet membrane protein, 0.6 nM [3H]C_.8-PAF (from Amersham or New England Nuclear; specific activity 120-180 Ci/mmol), with and without test compound, in "binding buffer” consisting of TME with 0.25% bovine serum albumin added (Sigma, RIA grade). The final volume of the assay was 100 ⁇ l.
  • the assay was conducted in Millititre-GVTM (Millipore Corp.) filtration plates; incubation time was for 60 minutes at room temperature (22-23°G).
  • Specific binding was operationally defined as the arithmetic difference between “total binding” of 0.6 nM [ ⁇ HJCi ⁇ -PAF (in the absence of added PAF) and “nonspecific binding” (in the presence of 1 ⁇ M PAF). After the prescribed incubation, platelet membranes were filtered under vacuum, and washed with 1 millilitre of "binding buffer”. The filters were dried and removed. The bound radioactivity was quantitated with a Berthold TLC-Linear Analyzer model LB2842.
  • Step 2 2-(3-pyridinyl ' .-3-tert-butoxycarbonyl-4-thiazolidinecarboxylic acid.
  • Step 4 1- r2-(3-pyridinyl)-3-tert-butoxycarbonyI-4-thiazolid-4-oylmethvn-5- phenylmethoxyindole.
  • Step 5 l-r2-(3-pyridinyl)-thiazolid-4-ovn-5-phenylmethoxyindole. .l-[2-(3-pyridinyl)-3-(ter ⁇ utoxycarbonyI)-4-thiazolid-4-oyl]-
  • Step 1 l-r2-(3-pyridinyl)thiazolid-4-oyl1indole. l-[2-(3-pyridinyl)thiazolid-4-oyl]indole was prepared as described as described i Example 1, except indole was used instead of 5-phenylmethoxyindole.
  • Step 2 l-r2-(3-pyridinyl)thiazolid-4-oyl1indole dihydrochloride.
  • step 1 The material prepared as in step 1 was dissolved in ether and treated with excess 4N HCl in dioxane. l-[2-(3-pyridinyl)thiazolid-4-oyl]indole dihydrochloride was isolated by filtration.
  • Example 5 Preparation of l-f2-(3-pyridinyl)thiazolid-4-ovn-4-chloroindole dihydrochloride l-[2-(3-pyridinyl)thiazolid-4-oyl]-4-chloroindole was prepared using the method of Example 1, except 4-chloroindole was used instead of 5-phenylmethoxyindole.
  • the dihydrochloride salt was prepared as described in Example 2.
  • Example 6 Preparation of l-f2-(3-pyridinvI)thiazolid-4-oyl]-4-bromoindole dihydrochloride l-[2-(3-pyridinyl)thiazolid-4-oyl]-4-bromoindole was prepared using the method of Example 1, except 4-bromoindole was used instead of 5-phenylmethoxyindole.
  • the dihydrochloride salt was prepared as described in Example 2.
  • Example 7 Preparation of l-r2-(3-pyridinyl)thiazolid-4-ovn-4-benzoylindole dihydrochloride. l-[2-(3-pyridinyl)thiazolid-4-oyl]-4-benzoylindole was prepared using the met of Example 1, except 4-benzoylindole was used instead of 5-phenylmethoxyindole. T dihydrochloride salt was prepared as described in Example 2.
  • Step 1 4-(3.4.5-trimethoxybenzoyl)indole.
  • the desired compound was prepared according to the method described in J. O Chem., 51: 5106-5110 (1986) for synthesis of 4-formylindole, except substituting N- methoxy-N-methyl-3,4,5-trimethoxybenzamide for dimethylformamide.
  • Step 2. 1 -r2-(3-pyridinyl)thiazolid-4-oyl1-4-(3 A5-trimethoxybenzoyl)indole.
  • l-[2-(3-pyridinyl)thiazolid-4-oyl]-4-(3,4,5-trimethoxybenzoyl)indole was prepared using the method of Example 1, except using 4-(3,4,5-trimethoxybenzoyl)ind instead of 5-phenylmethoxyindole.
  • IR(CDCI3) 3500,3100,2980,2920, 1695, 1595, 1470, 1450, 1370, 1255, 1175.
  • Example 14 Preparation of l-r2-(3-pyridinyl)thiazolid-4-ovn-6-fluoroindole.
  • l-[2-(3-pyridinyl)thiazolid-4-oyl]-6-fluoroindole was prepared using the method of Example 1, except 6-fluoroindole was used instead of 5-phenylmethoxyindole.
  • Example 16 Preparation of l-r2-(3-pyridinyl)thiazolid-4-oyl1-6-bromoindole. l-[2-(3-pyridinyl)thiazolid-4-oyl]-6-bromoindole was prepared using the method of Example 1 except 6-bromoindole was used instead of 5-phenylmethoxyindole.
  • Example 17 Preparation of l-r2-(3-pyridinvI)thiazoIid-4-ovn-6-benzoylindole.
  • l-[2-(3-pyridinyl)thiazolid-4-oyl]-6-benzoylindole was prepared using the metho of Example 1 except 6-benzoyloindole was used instead of 5-phenylmethoxyindole.
  • IR (CDCI3) 3500, 3300, 2960, 2940, 1710, 1705, 1450, 1395, 1350, 1205, 805.
  • the desired material was prepared using the method of Example 21, except usin 1-methylindole instead of 1,2-dimethylindole.
  • the dihydrochloride salt was prepared as described in Example 2.
  • the desired compound was prepared according to the method of Example 20, except substituting 5-phenylmethoxyindole for indole.
  • the oxalate salt was prepared as in Example 3.
  • Step 1 l-r2-(3-pyridinyl)thiazolid-4-oynimidazole.
  • Carbonyl diimidazole (0.724 g, 0.00447 mol) was added to a solution of 2-(3 pyridinyl)-3-terr-butoxycarbonyl-4-thiazolidinecarboxylic acid, prepared as described i Example 1, step 2 (1.32 g, 0.00426 mol) in methylene chloride (40 mL). After stirrin the reaction mixture for 3 hours the solution was extracted with saturated sodium chlorid and dried over magnesium sulfate. The solvent was removed in vacuo to afford 1.03 g o the desired product as a beige solid.
  • Step 1 Methyl 2.3-dimercaptopropenonate.
  • the reaction was then acidified to pH 2 by initial dropwise addition of 100 m saturated methanolic HCl (H2S evolution observed) followed by bubbling gaseous H into the reaction mixture until the desired pH was obtained. At this point, a thick whit precipitate was present.
  • the solution was stirred for an additional 4 hours and then concentrated in vacuo.
  • the resulting pasty residue was partitioned between 300 mL o water and 300 mL of ethyl ether.
  • the aqueous phase was extracted with ethyl ether (2 and the combined organic extracts washed once with brine and dried over magnesium sulfate.
  • the drying agent was filtered off and the filtrate concentrated in vacuo to yiel methyl 2,3-dimercaptopropenonate (28.5g, 86.5%) as a light yellow oil.
  • Methyl 2-(3-pyridinyl)-4- dithiolanecarboxylate was isolated in fractions 85-195 as 8.03 g (50.6% yield) of an orange oil.
  • o NMR (CDCI3, 300 MHz) ⁇ 3.45 (dd, 0.5H), 3.60 (dd, 0.5H), 3.65 (dd, 0.5H), 3.70 (dd,
  • Step 3 2-(3-pyridinyl)-4-dithiolanecarboxylic acid.
  • Step 4 l-r2-(3-pyridinyl)dithiolan-4-oyl1imidazole.
  • the desired compound was prepared according to the method of Example 25, step 1, except using 2-(3-pyridinyl)-4-dithiolanecarboxylic acid instead of 2-(3-pyridinyl)-3- tert-butoxycarbonyl-4-thiazolidinecarboxylic acid.
  • Step 5 l-r2-(3-pyridinvI)dithiolan-4-ovnindole.
  • Step 1 l-Ethyl-3-r2-(3-pyridinv ⁇ -3-tgrr-butoxycarbonylthiazolid-4-oyl1indole.
  • Potassium hexamethyldisilazide (1.2 mL, 0.5 M in toluene, 0.0006 mol) was added to a solution of 3-[2-(3-pyridinyl)-3-tert-butoxycarbonylthiazolid-4-oyl]indole prepared as described in Example 20 in tetrahydrofuran (10 mL) at -78°C. The mixtu was stirred for 20 minutes and then ethyl iodide (0.25 mL, 0.00031 mol) was added.
  • Step 2 l-Ethyl-3-r2-(3-pyridinyl)thiazolid-4-ovnindole oxalate.
  • 1 -Ethyl-3-[2-(3-pyridinyl)-3-tert-butoxycarbonylthiazolid-4-oyl]indole was deprotected with HCl in dioxane to give l-Ethyl-3-[2-(3-pyridinyl)thiazolid-4-oyl]indol oxalate.
  • the oxalate salt was prepared using the procedure described in Example 3.
  • Step 1 N-methoxy-N-methyl-2-(3-pyridinyl)-4-dithiolanecarboxamide.
  • N-methoxy-N-methyl amine (1.82 g, 0.018 mol) was added to a solution of 2-(3- pyridinyl)-4-dithiolanecarboxylic acid, prepared as described in Example 25 (2.97 g, 13.1 mol), dimethylaminopyridine (94 mg, 0.0008 mol), and N-methylmorpholine (4.5 mL, 0.0041 mol) in Dimethylformamide (15 mL) and methylene chloride (150 mL). Bis(2- oxo-3-oxazolidinyl)phosphinic chloride (5.0 g, 0.0197 mol) was then added and the clear solution stirred for 17 hours.
  • reaction mixture was partitioned between saturated aqueous ⁇ aHC ⁇ 3 (200 mL) and methylene chloride (400 mL). The organic phase was washed with brine and dried over MgSO4. The solvent was removed in vacuo and the residue chromatographed on silica gel eluting with 2:1 ethylacetate/hexanes to obtain t desired compound (2.21 g, 62%).
  • Step 2 l-tert-butoxycarbonyl-3-r2-(3-pyridinyl)dithiolan-4-ovnindole oxalate.
  • tert-Butyl lithium (19.4 mL, 1.7 M, 0.033 mol) was added to a solution of 1-ter butoxycarbonyl-3-bromo indole (4.96 g, 0.016 mol) in ether (170 mL) at -78°C. Twel min later N-methoxy-N-methyl-2-(3-pyridinyl)-4-dithiolanecarboxamide (1.45 g, 0.005 mol) in ether (20 mL) was added.
  • the suspension was stirred at -78°C for 1 hour and then allowed to warm to room temperature.
  • the mixture was partitioned between ether (350 mL) and saturated aqueous ammonium chloride solution (350 mL).
  • the organic phase was extracted with 200 mL of ethyl acetate and the combined organic phases we dried over MgSO4.
  • the solvent was removed in vacuo and the residue chromatograph on silica gel to give the desired product as a tan solid (1.14 g, 50%).
  • the oxalate salt w prepared as described in Example 3.
  • the desired compound was obtained along with the cis isomer from the sequenc described in Example 29. It was isolated from mixed fractions obtained during the chromatographic purification described in Example 29, step 2. The desired compound was purified by high pressure liquid chromatography on silica gel eluting with 2:1 ethyl acetate / hexanes. The oxalate salt was prepared as described in Example 3.
  • Step 1 l-Indol-3-yl-2-tgrt-butoxycarbonylamino-3-hydroxy propane.
  • Step 2 l-Indol-3-yl-2-tgrt-butoxycarbonylamino-3-thioacetoxy propane.
  • Di-isopropyl azodicarboxylate (3.48 mL, 0.017 mol) was added to a solution of triphenyl phosphine (4.63 g, 0.017 mol) in THF (75 mL).
  • the mixture was stirred at 0° for 30 min and then a solution of l-indol-3-yl-2-tgrt-butoxycarbonylamino-3-hydroxy propane, prepared as described above in step 1 (5.1 g, (0.017 mol) and thioacetic acid (1.26 mL, 0.176 mmol) in THF was added.
  • Step 3 l-Indol-3-yl-2-amino-3-mercaptopropane.
  • 3-Pyridinecarboxaldehyde (0.30 mL, 0.0032 mol) was added to a solution of 1- indol-3-yl-2-amino-3-mercaptopropane (650 mg) in ethanol (10 mL) and the mixture stirred overnight. The solvent was removed in vacuo and the residue chromatographed on silica gel eluting with 2:1 ethyl acetate / hexanes to the desired compound.
  • Step 5 3-r2-(3-pyridinyl)thiazolid-4-ylmethvnindole dihydrochloride.
  • Saturated HCl in ether (10 mL) was added to a solution of 3-[2-(3- pyridinyl)dithiolan-4-ylmethyl]indole in ethyl acetate (5 mL).
  • the resulting solid was collected by filtration and dried in vacuo to provide the desired compound (187 mg) as crystalline solid.
  • the desired compound was prepared using the procedure of Example 28, except using 6-phenyImethoxy-3-[2-(3-pyridinyl)thiazolid-4-oyl]indole prepared as described in Example 33, instead of 3-[2-(3-pyridinyl)thiazolid-4-oyl]indole.
  • the oxalate salt was prepared as described in Example 3.
  • Step 1 l-Phenylsulfonyl-3-r2-(3-pyridinyl)-3-rgrt-butoxycarbonylthiazolid-4-oyllindol o Powdered KOH (0.17 g, 0.0031 mol) was added to a solution of 3-[2-(3- pyridinyl)-3-tgrt-butoxycarbonylthiazolid-4-oyl]indole (0.25 g, 0.00061 mol), prepared described in Example 20, steps 1, 2 in dimethoxyethane (9 mL) at 0°C. Ten minutes later, benzene sulfonyl chloride (0.00067 mol) was added and the mixture stirred an additional 30 min.
  • Step 2 l-Phenylsulfonyl-3-r2-(3-pyridinyl)thiazolid-4-ovnindole.
  • the material prepared in step 1 above was deprotected using the method of
  • the desired compound was prepared according to the method of Example 36, except using methane sulfonyl chloride instead of benzene sulfonyl chloride.
  • the desired material was prepared using the method of Example 20, except usin 2-methyIindole instead of indole and methyl magnesium bromide instead of ethyl magnesium bromide.
  • the desired compound was prepared using the procedure of Example 28, except using 2-methyl-3-[2-(3-pyridinyl)thiazolid-4-oyl]indole prepared as described in Exampl 39, instead of 3-[2-(3-pyridinyl)thiazolid-4-oyl]indole.
  • IR (CDCI3) 3480, 3300, 3030, 2980, 2920, 1755, 1665, 1540, 1450, 1440, 1235.
  • the desired compound was prepared according to the method of Example 28, except using dimethyldicarbonate instead of di-tgrt-butyl dicarbonate.
  • the desired compound was prepared according to the method of Example 36, except using 4-chlorobenzoyl chloride instead of benzene sulfonyl chloride. Melting Point: 80-84°C.
  • the desired compound was prepared according to the method of Example 28, except using dibenzyldicarbonate instead of di-tgrt-butyldicarbonate.
  • the oxalate salt was prepared as described in Example 3.
  • the desired compound was prepared according to the method of Example 27, except using 2,2-dimethylpropionyl chloride instead of ethyl iodide. Melting Point: 78-80°C.
  • the desired compound was prepared according to the method of Example 36, except using diethylcarbamoyl chloride instead of benzenesulfonyl chloride, and using sodium hydride in tetrahydrofuran instead of potassium hydroxide in dimethoxyethane.
  • the desired material was prepared using the method of Example 20, except usin 7-phenyImethoxy indole instead of indole and methylmagnesium bromide instead of ethylmagnesium bromide.
  • the desired compound was prepared according to the method of Example 36, except using dimethylcarbamoyl chloride instead of benzenesulfonyl chloride and using 7-phenylmethoxy-3-[2-(3-pyridinyl)-3-tgrt-butoxycarbonylthiazolid-4-oyl]indole instead of 3-[2-(3-pyridinyl)-3-tgrr-butoxycarbonylthiazolid-4-oyl]indole.
  • the oxalate salt was prepared as described in Example 3. Melting Point: 78-84°C.
  • the desired compound was prepared according to the method of Example 36, except using dimethylcarbamoyl chloride instead of benzenesulfonyl chloride and using 6-phenylmethoxy-3-[2-(3-pyridinyl)-3-t g rt-butoxycarbonylthiazolid-4-oyl]indole instead of 3-[2-(3-pyridinyl)-3-tgrt-butoxycarbonylthiazolid-4-oyl]indole.
  • the desired compound was prepared using the procedure of Example 28, except using 7-phenylmethoxy-3-[2-(3-pyridinyl)thiazolid-4-oyl]indole prepared as described in
  • Example 33 instead of 3-[2-(3-pyridinyl)thiazolid-4-oyl]indole. Melting Point: 91 -96°C.
  • the desired compound was prepared according to the method of Example 27, except using N-morpholinocarbonyl chloride instead of ethyl iodide. Melting Point: 102-104°C.
  • the desired compound was prepared according to the method of Example 56, except using acetic anhydride instead of aceticformic anhydride. Melting Point: 170-173°C. NMR (CDCI3, 300 MHz): ⁇ 1.75 (s, 9H), 2.03 (s, 3H), 3.33 (m, 2H), 5.65 (m, IH), 7.4 (m, 4H), 8.15 (m, IH), 8.42 (m, IH), 8.50 (s, IH), 8.63 (m, 3H), 8.88 (bs, IH). Mass Spectrum (DCI/NH3): 452 (M+l)+.
  • the desired compound was prepared according to the method of Example 56, except using trimethylsilylisocyanate instead of acetic formic anhydride. Melting Point: 141-143°C. NMR (CDCI3, 300 MHz): ⁇ 1.72 (s, 9H), 3.28 (m, IH), 3.44 (m, IH), 4.40 (bs, IH), 5.6 (m, 0.25H), 5.73 (m, 0.75H), 6.09 (s, 0.75H), 6.19 (s, 0.25H), 7.40 (m, 4H), 8.15 (m, IH 8.42 (m, IH), 8.49 (s, IH), 8.60 (m, 2H), 8.84 (bs, 0.75H), 8.92 (bs, 0.25H). Mass Spectrum (DCI/NH3): 453 (M+H)+.
  • Potassium carbonate (0.82g, 5.9 mmol) was added to a solution in 3.0 mL of dimethylformamide of 3-[2-(3-pyridinyl)-3-tgrt-butoxycarbonylthiazolid-4-oyl]indole (0.39g, 0.70 mmol), prepared as in Example 20.
  • Neat 2-iodo-l,l,l-trifluoroethane (0.23g, 0.10 mmol) was added and the reaction mixture was stirred for 24 hours at ambient temperature and 24 hours at 40°C. The solids were removed by filtration and rinsed with methylene chloride.
  • Tetrahydrofuran and Butyllithium (2.5 M in hexanes, 0.2 mL, 0.50 mmol) was added.
  • the desired compound was prepared according to the method of Example 27 except substiting 4-morpholinecarbonyl chloride for iodoethane and substituting 2- methyl-3-[2-(3-pyridinyl)-3-tgrt-butoxycarbonylthiazolid-4-oyl]indole, prepared as in
  • the desired compound was prepared according to the method of Example 28 except using 2,5-dimethyl-3-[2-(3-pyridinyl)thiazolid-4-oyl]-indole, prepared as in
  • Example 66 instead of 3-[2-(3-pyridinyl)thiazolid-4-oyl]-indole.
  • the oxalate salt was prepared according to the method of Example 3. NMR (CDCI3, 300 MHz): ⁇ 1.69-1.73 (9H), 2.42 (s, 3H), 2.52 (s, 3H), 3.08-3.18 (m,
  • the desired compound was prepared according to the method of Example 27 except substituting 4-morpholinecarbonyl chloride for iodoethane and substituting 2,5- dimethyl-3-[2-(3-pyrdinyl)-3-tgrt-butoxycarbonylthiazolid-4-oyl]indole, prepared as in Example 20, steps 1 and 2, for 3-[2-(3-pyridinyl)-3-tgrt-butoxycarbonylthiazolid-4- oyl]indole.
  • the desired compound was prepared according to the method of Example 67 except substituting dimethylcarbamyl chloride for di-tgrt-butyldicarbonate.
  • the oxalate salt was prepared according to the method of Example 3.
  • Step 2 E- 1 -( 1 -pyrrolidinyl)-2- F 2-nitro-4-( 4-fluorophenoxy)phenynethylene.
  • the material prepared as in step 2 was dissolved in 80% aqueous acetic acid (320 mL, 4540 mmol) and the reaction mixture was warmed to 75°C.
  • Zinc dust (27g, 413 mmol) was added in 5 portions over 1 hour.
  • the resulting dark-brown suspension was warmed to 90°C and heated for two hours.
  • the reaction mixture was cooled to ambient temperature and diluted with ether.
  • the solids were removed by filtration through celite.
  • the filter cake was rinsed with H2O and ether.
  • the layers were separated and the organic phase was washed with H2O, with saturated aqueous NaHCO3 until basic, then once with brine, dried over Na2SO4, filtered, and concentrated in vacuo.
  • the crude product was purified by chromatography on silica gel to give 6-(4-fluorophenoxy)-indole (1.8g, 17%)
  • the desired compound was prepared according to the method of Example 20. except substituting 6-(4-fluorophenoxy)indole for indole. Melting Point: 189-191°C.
  • the desired compound was prepared according to the method of Example 36 except substituting dimethylcarbamoyl chloride for benzenesulfonyl chloride and substituting 3-[2-(3-pyridinyl)-3-tgrt-butoxycarbonylthiazolid-4-oyl]-6-(4- fluorophenoxy)indole, prepared as in Example 70 for 3-[2-(3-pyridinyl)thiazolid-4- oyl]indole.
  • the desired compound was prepared according to the method of Example 36 except substituting 4-morpholinecarbonyl chloride for benzenesulfonyl chloride and substituting 3-[2-(3-pyridinyl)-3-tgrt-butoxycarbonylthiazolid-4-oyl]-6- phenylmethoxyindole, prepared as in Example 34 for 3-[2-(3-pyridinyl)-3-tgrt- butoxycarbonyhhiazolid-4-oyl]indole.
  • the oxalate salt was prepared according to the method of Example 3.
  • 6-Phenylmethoxyindole (3.93g, 17.6 mmol), was suspended in acetone (350 mL), under N2 and cooled in an ice bath. 10% Palladium on carbon (0.80 g) was added, and the N2 atmosphere was replaced with H2 by alternately placing the reaction flask under vacuum and introducing H2 from a balloon. The cold bath was then removed and the reaction mixture stirred under positive H2 pressure for 16 hours. The reaction mixture was cooled in an ice bath, and N2 reintroduced. The reaction mixture was filtered through a pad of celite and concentrated in vacuo. The crude product was purified by chromatography on silica gel to give 6-hydroxyindole (1.70 g, 73%).
  • Step 2 6-(4-fiuorophenylmethoxy)indole.
  • 6-Hydroxyindole (0.90 g, 6.8 mmol) and potassium carbonate (1.04 g, 7.5 mmol were suspended in 13 mL of acetone.
  • 4-Fluorobenzyl bromide (0.93 mL, 7.5 mmol, pre filtered through basic alumina) was added dropwise via syringe.
  • the reaction mixture was heated at reflux under N2 atmosphere for 24 hours.
  • the reaction mixture was coole to ambient temperature and partitioned between H2O and methylene chloride.
  • the aqueous phase was extracted twice with methylene chloride.
  • the desired compound was prepared according to the method of Example 20, except substituting 6-(4-fluoromethoxyphenyl)indole for indole. Melting Point: 185-186°C.
  • the desired compound was prepared according to the method of Example 36, except substituting 3-[2-(3-pyridinyl)-3-tgrt-butoxycarbonylthiazolid-4-oyl]-6-(4- fluorophenylmethoxy)indole, prepared as in Example 74, for 3-[2-(3-pyridinyl)-3-tgrt- butoxycarbonylthiazoIid-4-oyl]indole, and substituting dimethylcarbamoyl chloride for benzenesulfonyl chloride. Melting Point: 71-74°C.
  • the desired compound was prepared according to the method of Example 74, step 2 except substituting 3-(chloromethyl)pyridine for 4-fluorobenzyl bromide.
  • Step 2 3-r2-(3-pyridinyl)thiazolid-4-oyn-6-(3-methylpyridinyl)indole.
  • the desired compound was prepared according to the method of Example 20 except substituting 6-(3-methylpyridinyl)-indole for indole.
  • Step 1 E-l-(l-pyrroIidinyl)-2-(4-bromo-2-nitrophenyl)ethylene.
  • the desired compound was prepared according to the method of Example 70, step 2 except substituting 4-bromo-2-nitrotoluene for 2-nitro-4-(4-fluorophenoxy)toluene.
  • the crude material was used with no further purification. Step 2. 6-Bromoindole.
  • step 1 The material obtained as in step 1 (32.9 g) was combined with Raney nickel 280 (32.9 g) and toluene (2.0 L) and stirred under a pressure of 4 atmospheres of hydrogen f 2 hours. The reaction mixture was filtered and concentrated in vacuo. The crude produc was purified by chromatography on silica gel to give 6-bromoindole (17.4 g, 78% yield from 4-bromo-2-nitrotoluene).
  • Step 3 6-Phenylethvnylindole. 6-Bromoindole (3.84 g, 19.6 mmol) was dissolved in triethylamine (40 mL). A catalytic amount of phenothiazine was added, and the solution was degassed by bubbling argon through it. Phenylacetylene (8.60 mL, 78.3 mmol) was added via syringe.
  • Step 4 3-r2-(3-pyridinyl ) thiazolid-4-ovn-6-phenylethvnvIindole.
  • the desired compound was prepared according to the method of Example 20 except substituting 6-phenylethynylindole for indole. Melting Point: 103-107°C.
  • the desired compound was prepared according to the method of Example 36 except substituting 3-[2-(3-pyridinyl)-3-tgrt-butoxycarbonylthiazolid-4-oyl]-6- phenylethynylindole, prepared as in Example 77 for 3-[2-(3-pyridinyl)-3-tgrt- butoxycarbonylthiazolid-4-oyl]indole, and substituting dimethylcarbamyl chloride for benzenesulfonyl chloride. Melting Point: 84-88°C.
  • Example 79 Preparation of 2-methyl-3-r2-(3-pyridinyl)thiazolid-4-ovn-6-phenylmethoxyindole.
  • the desired compound was prepared according to the method of Example 20 except substituting 2-methyl-6-phenylmethoxyindole for indole. Melting Point: 89-93°C.
  • the desired compound was prepared according to the method of Example 20, except substituting 6-methylindole for indole. Melting Point: 132-138°C.
  • the desired compound was prepared according to the method of Example 28 except substituting 3-[2-(3-pyridinyl)thiazolid-4-oyl]-6-methylindole, prepared as in
  • the desired compound was prepared according to the method of Example 3, except substituting 3-[2-(3-pyridinyl)thiazoIid-4-oyl]-6-methoxyindole for l-[2-(3- pyridinyl)-4-oyl]-indole. Melting Point: 115-118°C.
  • Example 84 Preparation of l-tgrt-butoxycarbonyl-3-r2-(3-pyridinyl)thiazolid-4-oyn-6-methoxyindole oxalate.
  • the desired compound was prepared according to the method of Example 28 except substituting 3-[2-(3-pyridinyl)thiazolid-4-oyl]-6-methoxyindole, prepared as in Example 82, for 3-[2-(3-pyridinyl)thiazolid-4-oyl]indole. Melting Point: 99-100°C.
  • Example 85 Preparation of 1 -dimethylcarbamoyl-3-r2-(3-pyridinyl)thiazolid-4-oyn-6-methoxyindole.
  • the desired compound was prepared according to the method of Example 36, except substituting 3-[2-(3-pyridinyl)-3-tgrt-butoxycarbonylthiazolid-4-oyl]-6- methoxyi ⁇ ndole, prepared as in Example 82 for 3-[2-(3-pyridinyl)-3-tgrt- butoxycarbonylthiazolid-4-oyl]indole, and substituting dimethylcarbamoyl chloride for benzenesulfonyl chloride.
  • Step 1 l-Trimethylsilyl-2-(2-nitro-4-biphenyl)-acetylene. 4-Bromo-3-nitrobiphenyl (5.0 g, 18 mmol) was dissolved in triethylamine (50 mL). Catalytic phenothiazine was added and the solution was degassed by bubbling argon through the solution for 45 min. Bis(triphenylphosphine)palladium(II) chloride (0.068 g, 0.10 mmol) and trimethylsilyl acetylene (5.0 mL, 36 mmol) were then added and the yellow solution was heated at 75°C for 4 hours.during which time it became a brown suspension. The reaction mixture was cooled to ambient temperature, the solids were removed by filtration, and the filtrate concentrated in vacuo. The crude product (6.11 g) was used without further purification.
  • Step 2 2-Nitro-4-biphenylacetaldehvde dimethyl acetal.
  • the material prepared as in Step 1 was dissolved in methanol (100 mL), and powdered KOH (5.6 g, 99 mmol) was added. The reaction mixture was heated at reflux for 17 hours. The solution was cooled to ambient temperature quenched with glacial acetic acid (6.0 L), and concentrated in vacuo. The residue was partitioned between H2O and methylene chloride. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give a brown oil. The crude material was purified by chromatography on silica gel to give 2-nitro-4-biphenylacetaldehyde dimethyl acetal (4.22 g, 74% yield for steps 1 and 2).
  • Step 4 6-Phenylindole.
  • the material prepared as in Step 3 was dissolved in 1:1 ethanol, water (16 mL), and concentrated HCl (1.0 mL) was added. The reaction mixture was stirred for 17 hours at ambient temperature, during which time a light-brown precipitate formed. The precipitate was filtered off to give 6-phenylindole (0.56 g) The filtrate was extracted with methylene chloride. The organic extract was dried over MgSO4, filtered, and concentrated in vacuo to a brown foam. The foam was crystallized trom ethanol to give 1.40 g of 6-phenylindole (total 1.96 g, 76% yield for steps 2-4). Step 5. 3-r2-(3-pyridinyl)thiazolid-4-oyn-6-phenylindole.
  • the desired compound was prepared according to the method of Example 20 except substituting 6-phenylindole for indole. Melting Point: 180-185°C.
  • Step 1 6-7grt-butyldimethylsilyloxyindole. 6-Hydroxyindole (0.419 g, 3.15 mmol), prepared as in Example 74, step 1, was dissolved in a mixture of methylene chloride (12 mL) and 2,6-lutidine (1.0 mL) and cooled in an ice-water bath. Tgrt-butyldimethylsilyl triflate (0.80 mL, 3.50 mmol) was added under N2 and the reacton mixture was stirred for 2 min, after which the cold bath was removed and stirring was continued for a further 20 min.
  • reaction mixture was poured into a mixture of aqueous pH 7 buffer (25 mL), and methylene chloride (25 mL).
  • the organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give the desired compound (0.679 g), which was used without further purification.
  • Step 2 3-r2-(3-pyridinyl)-3-tgrt-butoxycarbonylthiazolid-4-oyl1-6-tert- butyldimethylsilyloxyindole.
  • the desired compound was prepared according to the method of Example 20, steps 1 and 2, except substituting 6-tgrt-butyldimethylsilyloxyindole for indole.
  • Step 3 3-r2-(3-pyridinyl)thiazolid-4-oyl.-6-tgrt-butyldimethylsilvIoxyindole.
  • the desired compound was prepared according to the method of Example 36, step
  • Tetrabutylammomum fluoride (1.0M solution in tetrahydrofuran, 0.25 mL, 0.25 mmol) was added via syringe, and the reaction mixture was stirred for 1 hour. The reaction mixture was partitioned between ether and pH 7 aqueous buffer. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give 3-[2-(3- pyridinyl)thiazolid-4-oyl]-6-hydroxyindole (23 mg), as a yellow solid.
  • Step 1 3-r2-(3-pyridinvI)-3-tgrt-butoxycarbonylthiazolid-4-ovn-6-chloroindole.
  • the desired compound was prepared according to the method of Example 20, steps 1 and 2, except substituting 6-chloroindole for indole.
  • Step 2 l-dimethylcarbamoyl-3-r2-(3-pyridinyl)thiazolid-4-ovn-6-chloroindoIe.
  • the desired compound was prepared according to the method of Example 36 except substi ting 3-[2-(3-pyridinyl)-3-tgrt-butoxycarbonylthiazolid-4-oyl]-6- chloroindole, prepared as in step 1 for 3-[2-(3-pyridinyl)-3-tgrt-butoxycarbonylthiazolid- 4-oyl]indole, and substituting dimethylcarbamoyl chloride for benzenesulfonyl chloride.
  • Step 1 l-(4-morpholinocarbonyl)-3-r2-(3-pyridinyl)thiazolid-4-ovnindole.
  • the desired compound was prepared according to the method of Example 36, except substituting 4-morpholinecarbonyl chloride for benzenesulfonyl chloride.
  • Step 2. 1 -(4-mo holinocarbonyl)-3-r2-(3-pyridinyl)-3-formylthiazolid-4-oyllindole.
  • the desired compound was prepared according to the method of Example 56, except substituting 1 -(4-morpholinocarbonyl-3-[2-(3-pyridinyl)thiazolid-4-oyl]indole, prepared as in step 1, for l-tgrt-butoxycarbonyl-3-[2-(3-pyridinyl)thiazolid-4-oyl]indole.
  • Step 1 1 -Dimethylcarbamoyl-3-r2-(3-pyridinyl)thiazolid-4-oyl1indole.
  • the desired compound was prepared according to the method of Example 36 except substituting- 3-[2-(3-pyridinyl)-3-tgrt-butoxycarbonylthiazolid-4-oyl]-6- methylindole, prepared as in Example 80 for 3-[2-(3-pyridinyl)-3-tgrt- butoxycarbonylthiazolid-4-oyl]indole, and substituting dimethylcarbamoyl chloride for benzenesulfonyl chloride.
  • Step 2 l-Dimethylcarbamoyl-3-r2-(3-pyridinyl)-3-formylthiazolid-4-ovn-6- methylindole.
  • the desired compound was prepared according to the method of Example 56 except substituting 1 -Dimethylcarbamoyl-3-[2-(3-pyridinyl)thiazolid-4-oyl]-6- methylindole, prepared as in step 1, for l-tgrt-butoxycarbonyl-3-[2-(3- pyridinyl)thiazolid-4-oyl]indole.
  • Example 95 Preparation of l-dimethylcarbamoyl-3-ri-oxide-2-(3-pyridinyl)-3-formylthiazolid-4-oyll- indole.
  • l-Dimethylcarbamoyl-3-[2-(3-pyridinyl)-3-formylthiazolid-4-oyl]-indole (128 mg, 0.30 mmol), prepared as in Example 91, was dissolved in methylene chloride (3.0 mL). Titanium(IV) isopropoxide (0.10 mL, 0.33 mmol) and H2O (3.3x10-3 M in methylene chloride, 0.1 mL, 0.33 mmol) were added and the solution was cooled to -
  • the desired compound was prepared according to the method of Example 91, except that the cis isomer was isolated by chromatography on the Chromatatron (Si ⁇ 2; 1 mm; 97:3 to 95:5 chloroform, methanol).
  • the desired compound was prepared according to the method of Example 90, except substituting 1 -tgrt-butoxycarbonyl-3-[2-(3-pyridinyl)-3-acetylthiazolid-4- oyljindole, prepared as in Example 57 for l-tgrt-butoxycarbonyl-3-[2-(3-pyridinyl)-3- formylthiazolid-4-oyl]indole.
  • the desired compound was prepared according to the method of Example 57 except substituting l-Dimethylcarbamoyl-3-[2-(3-pyridinyl)thiazolid-4-oyl]-6- phenylmethoxyindole, prepared as in Example 52, for l-tgrt-butoxycarbonyl-3-[2-(3- pyridinyl)thiazolid-4-oyl]-6-phenylmethoxyindole.
  • the desired compound was prepared according to the method of Example 3, 5 except substituting l-Dimethylcarbamoyl-3-[2-(3-pyridinyl)-3-acetylthiazolid-4-oyl]-6- phenylmethoxyindole, prepared as in Example 99, for l-[2-(3-pyridinyl)thiazolid-4- oyl]indole.
  • Step 1 I -tgrt-butoxycarbonyl-3-r2-(3-pyridinyl)-3-trifluoroacetylthiazolid-4-ovnindole.
  • the desired compound was prepared according to the method of Example 56 except substituting trifluoroacetic anhydride for acetic formic anhydride. 0
  • the desired compound was prepared according to the method of Example 90 except substituting the material obtained as in step 1 for l-tgrt-butoxycarbonyl-3-[2-(3- pyridinyl)-3-formylthiazolid-4-oyl]indoIe. Chromatography on silica gel (98:2, then 95:5 5 chloroform, methanol) resolved the crude product into 2 sets of stereoisomers of unknown absolute stereochemistry.
  • the desired compound was prepared according to the method of Example 56 except substituting 1 -Dimethylcarbamoyl- 3- [2- (3-pyridinyl)thiazolid-4-oyl]indole, prepared as in Example 38 for l-tgrt-butoxycarbonyl-3-[2-(3-pyridinyl)thiazolid-4- oyl]indole, and trifluoroacetic anhydride for acetic formic anhydride. Chromatography on silica gel (50%, then 70% ethyl acetate, hexane; then ethyl acetate) afforded the cis isomer.
  • the desired compound was prepared according to the method of Example 3, except substituting cis l-dimethylcarbamoyl-3-[2-(3-pyridinyl)-3-trifluoroacetylthiazolid
  • the desired compound was prepared according to the method of Example 3, except substituting trans- 1 -dimethylcarbamoyl-3-[2-(3-pyridinyl)-3- trifluoroacetylthiazolid-4-oyl]indole, prepared as in Example 106, for l-[2-(3- pyridinyI)thiazolid-4-oyl]indole.
  • the desired compound was prepared according to the method of Example 56 except substituting l-Dimethylcarbamoyl-3-[2-(3-pyridinyl)thiazolid-4-oyl]-6- phenylmethoxyindole, prepared as in Example 52, for l-tgrt-butoxycarbonyl-3-[2-(3- pyridinyI)thiazolid-4-oyl]indole, and trifluoroacetic anhydride for acetic formic anhydride. Chromatography on silica gel (2:3, then 3:2 ethyl acetate, hexane; then ethyl acetate), resolved the crude product into two sets of isomers of unknown absolute stereochemistry.
  • the desired compound was prepared according to the method of Example 56 except substituting l-Dimethylcarbamoyl-3-[2-(3-pyridinyl)thiazolid-4-oyl]indole, prepared as in Example 38 for l-tgrt-butoxycarbonyl-3-[2-(3-pyridinyl)thiazolid-4- oyl]indole, and trimethylsilyl isocyanate for acetic formic anhydride.
  • the desired compound was prepared according to the method of Example 56 except substituting 1 -Dimethylcarbamoyl-3-[2-(3-pyridinyl)thiazolid-4-oyl]-6- phenylmethoxyindole, prepared as in Example 52 for l-tgrt-butoxycarbonyl-3-[2-(3- pyridinyl)thiazolid-4-oyl]-indole, and trimethylisocyanate for acetic formic anhydride.
  • the ester was hydrolyzed according to the method of Example 26, step 3 except substituting 2-(3-pyridinyl)-3-tgrt-butoxycarbonyl-4-oxazolidinecarboxylate methyl ester for methyl 2-(3-pyridinyl)-4-dithiolanecarboxylate.
  • Oxalyl chloride 0.39 mL, 44.5 mmol) was added dropwise and the reaction mixture was stirred for 10 min in the ice bath and 40 min at ambient temperature The orange-brown suspension was cooled in the ice bath and carried on without further purification.
  • Step 5 3-r2-(3-pyridinyl)-3-tgrt-butoxycarbonyloxazolid-4-oyllindole.
  • Step 6 l-Dimethylcarbamoyl-3-r2-(3-pyridinyl)oxazolid-4-oyllindole.
  • the desired compound was prepared according to the method of Example 36, except substituting 3-[2-(3-pyridinyl)-3-tgrt-butoxycarbonyloxazolid-4-oyl]-indole, prepared as in step 5 for 3-[2-(3-pyridinyl)-3-tgrt-butoxycarbonylthiazolid-4-oyl]-indole, and substituting dimethylcarbamoyl chloride for benzenesulfonyl chloride.
  • Step 7. 1 -IMmethylcarbamoyl-3-r2-(3-pyridinyl)-3-formyloxazolid-4-oyl1indoIe.
  • the desired compound was prepared according to the method of Example 56, except substituting l-Dimethylcarbamoyl-3-[2-(3-pyridinyl)oxazolid-4-oyl]indole, prepared as in step 6 for l-tgrt-butoxycarbonyl-3-[2-(3-pyridinyl)thiazolid-4-oyl]indole. Melting Point: 161.5-163.5°C.
  • Step 1 Methyl-2-(3-pyridinyl)-3-tgrt-butoxycarbonyl-4-thiazoIidinecarboxylate.
  • Step 3 r2-(3-pyridinyl)-3-tgrt-butoxycarbonvI-4-thiazolid-4-vn (1-tert- butoxycarbonylindol-3-yl)methanol.
  • Step 4 r2-(3-pyridinyl)thiazolid-4-yll (l-tgrt-butoxycarbonylindol-3-yl)methanol.
  • Step 2. Phenylsulfonyl-2-r2-(3-pyridinyl)-3-tgrt-butoxycarbonylthiazolid-4-oyll- indole.
  • the desired compound was prepared according to the method of Example 36, step
  • Step 1 3-r2-(3-pyridinyl)-3-tgrt-butylcarbonylthiazolid-4-ovnindole.
  • Ethylmagnesium bromide (3.0M in ether, 10.7 mL, 32.1 mmol) was added to a solution of indole (3.77 g, 32.1 mmol) in ether (100 mL).
  • the cloudy yellow-green solution was stirred for 15 min at ambient temperature, then zinc chloride (1.0M in ether, 32.2 ml, 32.2 mmol) was added and the resulting heterogenous solution was stirred for 0.5 hour at ambient temperature.
  • Step 2. 1 -(NJV-Dimethylcarbamoylmethyl)-3-r2-(3-pyridinyl)thiazolid-4-ovnindole.
  • the desired compound was prepared according to the method of Example 60, except substituting ⁇ , ⁇ -dimethylchloroacetamide for ethyl chloroacetate.
  • the desired compound was prepared according to the method of Example 60, except substituting methyl acrylate for ethyl chloroacetate.
  • Step 1 l-Carbomethoxyethyl-3-r2-(3-pyridinvI)-3-tgrt-Butoxycarbonyl-thiazolid-4- oyllindole.
  • Step 2 l-Carboxyethyl-3-r2-(3-pyridinyl)thiazolid-4-ovnindole.
  • l-Carboxyethyl-3-[2-(3-pyridinyl)-3-tgrt-butoxycarbonyl-thiazolid-4-oyl]indole (2.29 g, 4.8 mmol) was deprotected with 4 M hydrochloric acid in dioxane as described in Example 1, step 5 to yield l-Carboxyethyl-3-[2-(3-pyridinyl)thiazolid-4-oyl]indole.
  • the desired compound was prepared according to the method of Example 119, except substituting l-Ethoxycarbonylmethyl-3-[2-(3-pyridinyl)-3-tgrt- butoxycarbonyhhiazolid-4-oyl]indole for l-Carbomethoxyethyl-3-[2-(3-pyridinyl)-3-tgrt- butoxycarbonylthiazolid-4-oyl]indole.
  • the desired compound was prepared according to the method of Example 86, steps 1-4, except substituting methyl 4-chloro-3-nitrobenzoate for 4-Bromo-3- nitrobiphenyl.
  • the desired compound was prepared according to the method of Example 116, step 1, except substituting methyl indole-6-carboxylate for indole.
  • the desired compound was prepared according to the method of Example 3, except substituting 1 -Dimethylcarbamoyl-3-[2-(3-pyridinyl)thiazolid-4-oyl]-6- phenylmethoxyindole, prepared as in Example 52 for l-[2-(3-pyridinyl)thiazolid-4- oyl]indole.

Abstract

L'invention se rapporte à des composés d'indole, qui sont substitués aux positions 1 ou 3 par un groupe (pyrid-3-yl)thiazolid-4-yl alkyl-, (pyrid-3-yl)thiazolid-4-oyl)-, (pyrid-3-yl)dithiolan-4-yl)alkyl- ou (pyrid-3-yl)dithiolan-4-oyl)- et qui constituent de puissants inhibiteurs du facteur d'activation des plaquettes et sont utiles dans le traitement des troubles associés au facteur d'activation des plaquettes, tels que choc septique, syndrome de la détresse respiratoire, inflammations aiguës, immunité cellulaire retardée, parturition, maturation des poumons du foetus et différenciation cellulaire.
EP19920906944 1991-02-20 1992-02-14 Indoles useful as platelet activating factor antagonists Withdrawn EP0574494A4 (en)

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US07/658,134 US5120749A (en) 1991-02-20 1991-02-20 Platelet activating antagonists

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US5120749A (en) * 1991-02-20 1992-06-09 Abbott Laboratories Platelet activating antagonists
CH687764A5 (de) * 1992-07-02 1997-02-14 Lonza Ag Gampel Wallis Geschof Verfahren zur Herstellung von 7-Acylindolen.
US5288743A (en) * 1992-11-20 1994-02-22 Abbott Laboratories Indole carboxylate derivatives which inhibit leukotriene biosynthesis
US5486525A (en) * 1993-12-16 1996-01-23 Abbott Laboratories Platelet activating factor antagonists: imidazopyridine indoles
US5811425A (en) * 1997-03-04 1998-09-22 Abbott Laboratories Heterocyclic compounds as COX-2 inhibitors
US6448353B1 (en) 2000-02-08 2002-09-10 3M Innovative Properties Company Continuous process for the production of controlled architecture materials
ES2222828B1 (es) * 2003-07-30 2006-04-16 Laboratorios Del Dr. Esteve, S.A. Derivados de 1-sulfonilindoles, su preparacion y su aplicacion como medicamentos.
US8822513B2 (en) 2010-03-01 2014-09-02 Gtx, Inc. Compounds for treatment of cancer
US9447049B2 (en) 2010-03-01 2016-09-20 University Of Tennessee Research Foundation Compounds for treatment of cancer
ES2927660T3 (es) * 2008-06-16 2022-11-10 Univ Tennessee Res Found Compuestos para el tratamiento del cáncer
US9029408B2 (en) 2008-06-16 2015-05-12 Gtx, Inc. Compounds for treatment of cancer
KR20120130777A (ko) 2010-03-01 2012-12-03 유니버시티 오브 테네시 리서치 파운데이션 암 치료용 화합물
JP6835472B2 (ja) 2013-03-05 2021-02-24 ユニバーシティ オブ テネシー リサーチ ファウンデーション 癌の処置のための組成物
AU2021215709A1 (en) 2020-02-04 2022-09-01 Mindset Pharma Inc. 3-pyrrolidine-indole derivatives as serotonergic psychedelic agents for the treatment of CNS disorders

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EP0279681A2 (fr) * 1987-02-20 1988-08-24 Yamanouchi Pharmaceutical Co. Ltd. Dérivés de carboxamides hétérocycliques saturés
EP0335381A1 (fr) * 1988-03-30 1989-10-04 Boehringer Ingelheim Kg Imidazoles substitués en 2,3,4 et 1,2,4-triazoles substitués en 3,4,5, leur préparation et leur utilisation
EP0350145A2 (fr) * 1988-04-28 1990-01-10 Yamanouchi Pharmaceutical Co. Ltd. Derivés de Pyridylthiazolidine carboxamide et intermédiaires et leur production
GB2225012A (en) * 1988-11-18 1990-05-23 Lorenzini Inst Biochim Ital Indole derivatives, their preparation and use as medicaments

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DK151884C (da) * 1979-03-07 1988-06-13 Pfizer Analogifremgangsmaade til fremstilling af 3-(1-imidazolylalkyl)indolderivater eller farmaceutisk acceptable syreadditionssalte deraf
FR2601016B1 (fr) * 1986-07-04 1988-10-07 Rhone Poulenc Sante Nouveaux derives du 1h,3h-pyrrolo (1,2-c) thiazole, leur preparation et les compositions pharmaceutiques qui les contiennent
US5120749A (en) * 1991-02-20 1992-06-09 Abbott Laboratories Platelet activating antagonists

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EP0279681A2 (fr) * 1987-02-20 1988-08-24 Yamanouchi Pharmaceutical Co. Ltd. Dérivés de carboxamides hétérocycliques saturés
EP0335381A1 (fr) * 1988-03-30 1989-10-04 Boehringer Ingelheim Kg Imidazoles substitués en 2,3,4 et 1,2,4-triazoles substitués en 3,4,5, leur préparation et leur utilisation
EP0350145A2 (fr) * 1988-04-28 1990-01-10 Yamanouchi Pharmaceutical Co. Ltd. Derivés de Pyridylthiazolidine carboxamide et intermédiaires et leur production
GB2225012A (en) * 1988-11-18 1990-05-23 Lorenzini Inst Biochim Ital Indole derivatives, their preparation and use as medicaments

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CA2100682A1 (fr) 1992-08-21
EP0574494A4 (en) 1994-07-06
IL100850A0 (en) 1992-11-15
EP0499987A1 (fr) 1992-08-26
JPH06505273A (ja) 1994-06-16
AU652433B2 (en) 1994-08-25
AU1434292A (en) 1992-09-15
US5382670A (en) 1995-01-17

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